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Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor

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Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor International Journal of Molecular Sciences Article Selective Inhibition of Heparan Sulphate and Not Chondroitin Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor Marissa L. Maciej-Hulme 1,*,† , Eamon Dubaissi 2, Chun Shao 3, Joseph Zaia 3 , Enrique Amaya 2 , Sabine L. Flitsch 4 and Catherine L. R. Merry 1,*,‡ 1 Materials Science Centre, School of Materials, The University of Manchester, Grosvenor St., Manchester M1 7HS, UK 2 Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK; [email protected] (E.D.); [email protected] (E.A.) 3 Center for Biomedical Mass Spectrometry, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA; [email protected] (C.S.); [email protected] (J.Z.) 4 School of Chemistry & Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK; [email protected] * Correspondence: [email protected] (M.L.M.-H.); [email protected] (C.L.R.M.) † Current address: Department of Nephrology, Radboudumc, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands. ‡ Current address: Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, Citation: Maciej-Hulme, M.L.; Nottingham NG7 2RD, UK. Dubaissi, E.; Shao, C.; Zaia, J.; Amaya, E.; Flitsch, S.L.; Merry, C.L.R. Abstract: The glycosaminoglycan, heparan sulphate (HS), orchestrates many developmental pro- Selective Inhibition of Heparan cesses. Yet its biological role has not yet fully been elucidated. Small molecule chemical inhibitors Sulphate and Not Chondroitin can be used to perturb HS function and these compounds provide cheap alternatives to genetic Sulphate Biosynthesis by a Small, Soluble Competitive Inhibitor. Int. J. manipulation methods. However, existing chemical inhibition methods for HS also interfere with Mol. Sci. 2021, 22, 6988. https:// chondroitin sulphate (CS), complicating data interpretation of HS function. Herein, a simple method doi.org/10.3390/ijms22136988 for the selective inhibition of HS biosynthesis is described. Using endogenous metabolic sugar pathways, Ac4GalNAz produces UDP-GlcNAz, which can target HS synthesis. Cell treatment with Academic Editors: Chiara Schiraldi, Ac4GalNAz resulted in defective chain elongation of the polymer and decreased HS expression. Donatella Cimini and Annalisa Conversely, no adverse effect on CS production was observed. The inhibition was transient and La Gatta dose-dependent, affording rescue of HS expression after removal of the unnatural azido sugar. The utility of inhibition is demonstrated in cell culture and in whole organisms, demonstrating that this Received: 24 May 2021 small molecule can be used as a tool for HS inhibition in biological systems. Accepted: 19 June 2021 Published: 29 June 2021 Keywords: heparan sulfate; azido sugar; glycosaminoglycan; carbohydrate biosynthesis; small molecule inhibitor; biorthogonal chemistry Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Heparan sulphate (HS) is a prevalent glycosaminoglycan (GAG) attached to protein cores (proteoglycans) on the cell surface of almost every cell type. HS proteoglycans form an integral part of the extracellular matrix with important roles in development [1], home- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. ostasis [2,3] and disease [4,5]. HS is involved in cell-cell and cell-matrix communication, This article is an open access article fine-tuning cellular responses to the extracellular milieu. distributed under the terms and HS biosynthesis consists of a repeating disaccharide unit structure of glucuronic conditions of the Creative Commons acid–N-acetylglucosamine (GlcA-GlcNAc) polymerised by the exostoses enzyme complex Attribution (CC BY) license (https:// (EXT1/2) from UDP-GlcA and UDP-GlcNAc active nucleotide donor sugars [6–8]. During creativecommons.org/licenses/by/ this process the N-deacetylase/N-sulphotransferase (NDST) enzymes work in tandem to 4.0/). begin modification of the nascent chain. The NDST enzymes can replace the acetyl group Int. J. Mol. Sci. 2021, 22, 6988. https://doi.org/10.3390/ijms22136988 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 11 Int. J. Mol. Sci. 2021this, 22 process, 6988 the N-deacetylase/N-sulphotransferase (NDST) enzymes work in tandem to 2 of 11 begin modification of the nascent chain. The NDST enzymes can replace the acetyl group on GlcNAc with a sulphate [9], often providing the gateway step for further modifications of the chain. Additionally, the NDSTs are also involved in control of HS chain length [10] with NDST shownon GlcNActo be co- withlocalised a sulphate with EXT2 [9], often [11]. providing During extension the gateway of the step backbone, for further modifications several other chemicaof thel chain.modifications Additionally, are possible, the NDSTs resulting are also in fine involved patterning in control of the of chain HS chain length [10] with NDST shown to be co-localised with EXT2 [11]. During extension of the backbone, where the functionality of HS is encoded. O-sulphotransferases (OSTs) modify the HS several other chemical modifications are possible, resulting in fine patterning of the chain chain at the 2-, 6- and 3-O position or epimerisation of GlcA to iduronic acid (IdoA) by where the functionality of HS is encoded. O-sulphotransferases (OSTs) modify the HS C5-epimerase can occur. Together, these enzymes contribute to HS functionality by influ- chain at the 2-, 6- and 3-O position or epimerisation of GlcA to iduronic acid (IdoA) by C5- encing the fine patterning of the chain [12]. epimerase can occur. Together, these enzymes contribute to HS functionality by influencing Despite its widespread role in biology, few chemical tools exist for the manipulation the fine patterning of the chain [12]. of HS function, with those available often interfering with chondroitin sulphate/dermatan Despite its widespread role in biology, few chemical tools exist for the manipulation sulphate (CS/DS) pathways simultaneously. Methods to ablate HS exist via targeted ge- of HS function, with those available often interfering with chondroitin sulphate/dermatan netic deletion of biosynthetic HS enzymes [6,7]. However, genetic manipulation is costly sulphate (CS/DS) pathways simultaneously. Methods to ablate HS exist via targeted and labour intensive with embryonic lethality in null mutant animals [7], posing chal- genetic deletion of biosynthetic HS enzymes [6,7]. However, genetic manipulation is lenges for post-embryoniccostly and labouranalysis. intensive In contrast, with chemical embryonic approaches lethality inoffer null cheap, mutant user animals- [7], posing friendly alternatives,challenges which for either post-embryonic perturb sulphation analysis. of Inthe contrast, chain [13,14] chemical or compete approaches with offer cheap, user- endogenous substratesfriendly involved alternatives, in HS which assembly, either such perturb as amino sulphation sugar of derivatives the chain [[15,16]13,14]or compete with and mimics of tetrasaccharideendogenous substrates linkages [17 involved–20]. However, in HS assembly, the additional such as effect amino on sugar CS/DS derivatives [15,16] synthesis can complicateand mimics data of interpretation tetrasaccharide particularly linkages [17 when–20]. both However, GAGs the are additional displayed effect on CS/DS on the proteoglycansynthesis of inte canrest complicate [21]. data interpretation particularly when both GAGs are displayed Azido sugarson theand proteoglycanother bio-orthogonal of interest chemistry [21]. approaches have been demon- strated as useful functionalisedAzido sugars chemical and other probes bio-orthogonal to label N-glycans chemistry [22] approaches, O-GlcNAc have modi- been demonstrated fications [23], mucinas useful type O functionalised-GalNAc glycans chemical [24] and probes sialic toacid label moietiesN-glycans [25]. Tetra [22],- O-GlcNAcacet- modifica- ylated N-azidoacetylgalactosaminetions [23], mucin type (Ac O-GalNAc4GalNAz) glycanscan be metabolically [24] and sialic converted acid moieties to UDP [25].- Tetra-acetylated GlcNAz and UDPN-azidoacetylgalactosamine-GalNAz via the GalNAc salvage (Ac4GalNAz) pathway can [23] be metabolically, potentiating converted its use in to UDP-GlcNAz GAG synthesis (andFigure UDP-GalNAz 1). via the GalNAc salvage pathway [23], potentiating its use in GAG synthesis (Figure1). Figure 1. Figure(A) Structure 1. (A) Structure of tetra-acetylated of tetra-acetylatedN-azidoacetylgalactosamine. N-azidoacetylgalactosamine. (B) Schematic (B) Schematic of biological of biological azido sugar precursor productionazido for GAGsugar synthesis.precursor production Ac4GalNAz for travels GAG synthesis. across the Ac cell4GalNAz membrane travels and across enters the the cell cytoplasm. membrane Endogenous deacetylasesand removeenters the the cytoplasm acetyl protective. Endogenous groups deacetylases leaving GalNAz, remove ready the toacetyl enter protec the GalNActive groups salvage leaving pathway. After a cascadeGalNAz, of enzymes, ready both to enter UDP-GalNAz the GalNAc and salvage UDP-GlcNAz pathway. After are produced, a cascade whichof enzymes, target both CS/DS UDP and- potentially HS biosynthesisGalNAz respectively. and UDP-GlcNAz
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